Immune responses in the lung are essential for protecting against respiratory pathogens which constitute the most prevalent cause of illness and infant/child mortality worldwide. The majority of T cells in the lung comprise the memory subset, which is generated during a previous antigen exposure, and is functionally enhanced compared to naive T cells which reside in lymphoid tissues. Memory T cells resident in lung tissue can potentially mediate rapid in situ immunity for clearing respiratory pathogens; however, there are no strategies to specifically promote lung-resident immune responses. My laboratory has identified a novel population of influenza-specific memory CD4 T cells that are retained and remain resident in lung tissue, and can promote rapid, optimal protection to influenza virus infection compared to circulating memory T cells found in spleen and lymphoid tissue. These tissue-resident memory CD4 T cells (designated CD4 TRM) are distinct from circulating effector-memory T cells (TEM), and constitute a new memory subset analogous to tissue-resident memory CD8 T cell subsets (CD8 TRM) identified in skin, intestines and other mucosal sites. We have used innovative in vivo antibody labeling and imaging approaches to study lung CD4 TRM in situ, as well as RNA next-gen sequencing to compare lung TRM to spleen TEM to identify key pathways involved in lung CD4 TRM generation and retention. We have uncovered a novel role for the integrin CD11d, specifically expressed in mouse and human lung CD4 TRM, in sustaining T cell activation and differentiation, and a role for inflammatory signals via type I IFN in lung TRM maintenance. Our central hypothesis is that generation and tissue targeting of lung CD4 TRM involves antigenic and inflammatory signals in the lung coupled with T cell intrinsic expression of CD11d, while maintenance of lung TRM relies on low-level inflammation. In the proposed research, we will use murine targeted deletion models, imaging, and bioinformatics to investigate the roles of inflammation, antigen stimulation, and CD11d expression in the generation and maintenance of lung TRM. Results from these studies will provide crucial insights for targeting lung resident populations to enhance protective immunity, and for understanding maintenance of immune homeostasis in the respiratory tract.